doi:10.1038/81426
November 2000 Volume 3 Number Supp p 1165
The Hodgkin-Huxley theory of the action
potential
Michael Häusser
The author is in the Department of Physiology, University College London, Gower
Street, London WC1E 6BT, UK. e-mail: m.hausser@ucl.ac.uk
The Hodgkin-Huxley (H-H) theory of the action potential, formulated 50
years ago, remains one of the great success stories in biology, and
ranks among the most significant conceptual breakthroughs in
neuroscience. Together with the artificial neural networks of McCulloch
and Pitts, the quantal theory of Katz, and the cable theory of Rall, all
developed at around the same time, the H-H theory provided the
foundation for modern computational neuroscience.
The theory was the culmination of an intense experimental and
theoretical collaboration between Hodgkin and Huxley, from 1938 to the
publication in 1952 of their five landmark papers in the Journal of
Physiology. The stage was set by four key developments. First, Cole and
Curtis demonstrated that the action potential is associated with a large
increase in membrane conductance1. Second, Hodgkin and Huxley2
made the first intracellular recording of an action potential ( Fig. 1a).
This demonstrated directly that the action potential exceeds zero mV,
rejecting Bernstein's hypothesis3 that the underlying increase in
membrane permeability is non-selective. Hodgkin and Katz4 explained
the overshooting action potential by showing that it results from an
increase in sodium permeability (validating the neglected work of
Overton5). Finally, Hodgkin, Huxley and Katz (following Cole and
Marmont) developed a voltage-clamp circuit to enable quantitative
measurement of ionic currents from squid axon.
Hodgkin and Huxley then showed that step
depolarizations of the squid axon trigger an inward
current followed by an outward current. Using ionic
substitution, they demonstrated that this net current
could be separated into two distinct components, a
rapid inward current carried by Na+ ions, and a more
slowly activating outward current carried by K+ ions.
From experiments using ingenious voltage-clamp
protocols, they concluded that these two currents
result from independent permeability mechanisms for
Na + and K+ with conductances changing as a function
of time and membrane potential. This was a stunning
conceptual breakthrough, later termed the 'ionic
hypothesis,' a unifying framework for the field that
triggered the search for the underlying molecular
structures.
Their most remarkable achievement, however, was the
empirical representation of the experimental data in a
quantitative model6, the first complete description of
the excitability of a single cell. They modeled the
observed smooth current changes in terms of pores or
channels that were either open or closed, and by using
a statistical approach generated predictions for the
probability of channels being open. They represented
total ionic current as the sum of separate Na+, K+ and
leak currents:
where
separate equations for the gating variables m and h
(for activation and inactivation of gNa) or n (for
activation of gK) describe all the smoothly varying
voltage and time dependence of the kinetics. Thus, the
H-H model links the microscopic level of ion channels
to the macroscopic level of currents and action
potentials.
The model could reproduce and explain a remarkable
range of data from squid axon, including the shape and
propagation of the action potential, its sharp threshold,
refractory period, anode-break excitation,
accommodation and subthreshold oscillations. With
minor parameter changes, the model could describe
many channel types, underlining the generality of their
approach. Even today, most biophysical spiking models
are based on the H-H equations.
Like any good theory, the H-H model inspired many
new experiments. Armstrong and Bezanilla verified the
prediction of gating charge movement. Hille and others
confirmed that Na+ and K+ channels were separate
molecular entities with different pore sizes. This was
validated by single-channel recording of the behavior
of individual Na+ and K+ channels, and by cloning of
separate families of Na + and K+ channels. Naturally,
experiments over the last few decades also revealed
phenomena incompatible with the original H-H model,
such as the dependence of inactivation on activation
(see ref. 7).
What have computational neuroscientists learned from
Hodgkin and Huxley? First, they chose the right model
system. The squid axon offered technical advantages
due to its size and relative simplicity, with only two
types of voltage-gated conductances. Second, the H-H
model introduced the power of computers for solving
quantitative problems in neuroscience. Third, they
chose the right level of detail for the model. As
Hodgkin and Huxley were careful to point out, the fits
of the equations to the experimental data were not
perfect, and could easily have been improved by
adding more parameters. The H-H model thus
compactly captured the essence of the behavior.
Finally, perhaps their most important and intangible
influence was the style of their discovery. The H-H
model was so elegant and unprecedented in the
quantitative and complete nature of its description that
it provided an intellectual framework for biophysical
and modeling work that would influence the field for
decades. Moreover, their collaboration exemplified a
balance between experiment and theory that has rarely
been matched.
REFERENCES
1. Cole, K. S. & Curtis, H. J. J. Gen. Physiol. 22, 649-670
(1939). | ChemPort |
2. Hodgkin, A. L. & Huxley, A. F. Nature 144, 710-712
(1939).
3. Bernstein, J. Pflügers Arch. Ges. Physiol. 92, 521-562
(1902).
4. Hodgkin, A. L. & Katz, B. J. Physiol. (Lond.) 108, 37-77
(1949). | PubMed | ISI |
5. Overton, E. Pflügers Arch. Ges. Physiol. 92, 346-386
(1902).
6. Hodgkin, A. L. & Huxley, A. F. J. Physiol. (Lond.) 117, 500544 (1952). | ISI |
7. Hille, B. Ionic Channels of Excitable Membranes (Sinauer,
Sunderland, Massachusetts, 1992).